High risk breast cancer (HRBC), defined by the presence of &10 involved lymph nodes, large primary tumor or inflammatory disease, is associated with less the 50% survival at 5 years from diagnosis despite adjuvant therapy. Possible explanations for the aggressive cancer phenotype include a high prevalence of inherited mutations and/or a unique interaction between inherited and environmental risk factors. Approximately 7% of breast cancer (BC) cases are due to highly penetrant inherited susceptibility mutations (ISMs). The cumulative risk for developing BC for a carrier of an ISM is estimated to be 59% by age 50 years and 83% by age 70 years. The cloning of the BRCA1 gene on chromosome 17q, and BRCA2 on chromosome 13q, provides the opportunity to examine the influence of BRCA genotype on BC phenotype. The frequency of BRCA1 mutations in the general population has been estimated a 1:300 to 1:800. A clinical feature of hereditary cancers is occurrence at an early age. Specific BRCA1 and BRCA2 mutations were detected in 29% of Jewish women who developed BC before the age of 42. The median age of HRBC patients participating in high dose chemotherapy (HDCT) protocols at the study center is 42 years, 15 years lower than the median (57 years) for unselected BC cases. Preliminary data suggests that HRBC patient tumors have adverse prognostic features including p53 mutation, hormone receptor negativity, high histologic grade and increased proliferation. High-grade tumors have also been associated with specific ISMs, although genetic modifier loci and somatic mutations are likely to influence the clinical features at presentation, and who were treated in a uniform manner with HDCT. We propose to evaluate family history, personal risk factors, and genetic determinants (germline BRCA1 and BRCA2 genotype in this project, other candidate loci in future studies) in an attempt to explain the over-representation of younger patients in the HRBC cohort. We will also determine whether germline mutations and or somatic genetic changes (allelic deletion) and tumor biomarkers (ER/PR, p53, c-erbB-2 and proliferation indices) are correlated with clinical outcome. Such analyses may identify HRBC patients expected to most benefit form HDCT. Defining whether specific BRCA genotypes influence prognosis may contribute to our understanding of the phenotypic heterogeneity seen in hereditary cancer syndromes, while helping characterize the proportion of apparently sporadic BC for which may be an underlying genetic predisposition.